tbuckley/cabot-search huggingface dataset:
Waiting for Big Changes in Limited-Stage Small-Cell Lung Cancer: For Now, More of the Same
Authors: Matthew P. Deek, Missak Haigentz, Salma K. Jabbour
Journal: Journal of Clinical Oncology (2023)

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology , to patients seen in their own clinical practice. Concurrent chemoradiotherapy remains central to the treatment of limited-stage small-cell lung cancer (SCLC). SCLC is one of the few tumors treated with twice-daily radiotherapy (RT) in the primary definitive setting, a regimen that was established when Intergroup 0096 demonstrated its superiority over once-daily RT. However, questions remained about the optimal chemoradiotherapy regimen given the low RT dose used in the once-daily RT arm of Intergroup 0096. CALGB 30610/RTOG 0538 and CONVERT attempted to establish whether dose-escalated once-daily RT was superior to twice-daily RT in limited-stage SCLC. Although both studies showed similar survival between treatment regimens, once-daily RT was not found to be superior to twice-daily RT, and trial design limited the ability to conclude dose-escalated once-daily RT as noninferior to twice-daily RT. Thus, twice-daily RT with concurrent chemotherapy remains a standard of care in limited-stage SCLC.
Stochastic fate decisions of HSCs after transplantation: early contribution, symmetric expansion, and pool formation
Authors: Stefan Radtke, Mark R Enstrom, Dnyanada Pande, Elizabeth R Duke, Erwing Fabian Cardozo Ojeda, Ravishankar Madhu, Staci Owen, Greta Kanestrom, Margaret Lee Cui, Anai M Perez, Joshua T Schiffer, Hans-Peter Kiem
Journal: Blood (2023)
5-Year Follow-Up Supports Curative Potential of Axicabtagene Ciloleucel in Refractory Large B-Cell Lymphoma (ZUMA-1)
Authors: Sattva S. Neelapu, Caron A. Jacobson, Armin Ghobadi, David B Miklos, Lazaros J. Lekakis, Olalekan O. Oluwole, Yi Lin, Ira Braunschweig, Brian T. Hill, John M. Timmerman, Abhinav Deol, Patrick M Reagan, Patrick Joseph Stiff, Ian W. Flinn, Umar Farooq, Andre Goy, Peter McSweeney, Javier Munoz, Tanya Siddiqi, Julio C. Chavez, Alex F. Herrera, Nancy L. Bartlett, Adrian A. Bot, Rhine R. Shen, Jinghui Dong, Kanwarjit Singh, Harry Miao, Jenny J. Kim, Yan Zheng, Frederick L. Locke
Journal: Blood (2023)

In phase 2 of ZUMA-1, a single-arm, multicenter, registrational trial, axicabtagene ciloleucel (axi-cel) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy demonstrated durable responses at 2 years in patients with refractory large B-cell lymphoma (LBCL). Here, we aimed to assess survival and safety in ZUMA-1 after 5 years of follow-up. Eligible adults with refractory LBCL (diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma) received lymphodepleting chemotherapy followed by axi-cel infusion targeted at 2×106 cells/kg. Investigator-assessed response, updated survival, safety, and pharmacokinetic outcomes were assessed in treated patients. The objective response rate in the 101 treated patients was 83% (58% complete response rate), and with a median follow-up of 63.1 months, responses were ongoing at data cutoff in 31%. Median overall survival (OS) was 25.8 months and the estimated 5-year OS rate was 42.6%. Disease-specific survival (excluding deaths unrelated to disease progression) estimated at 5 years was 51.0%. No new serious adverse events or deaths related to axi-cel were observed after additional follow-up. Peripheral blood B cells were detectable in all evaluable patients at 3 years with polyclonal B-cell recovery in 91%. Ongoing responses at 60 months were associated with early CAR T-cell expansion. In conclusion, this 5-year follow-up analysis of ZUMA-1 demonstrates sustained overall and disease-specific survival, with no new safety signals in patients with refractory LBCL. Protracted B-cell aplasia was not required for durable responses. These findings support the curative potential of axi-cel in a subset of patients with aggressive B-cell lymphomas. ClinicalTrials.gov, number NCT02348216
Dual targeting of CD19 and CD22 with Bicistronic CAR-T cells in Patients with Relapsed/Refractory Large B Cell Lymphoma
Authors: Claire Roddie, Lazaros J. Lekakis, Maria A. V. Marzolini, Aravind Ramakrishnan, Yiyun Zhang, Yanqing Hu, Vijay G R Peddareddigari, Nushmia Z Khokhar, Robert W Chen, Silvia Basilico, Meera Raymond, Frederick Arce Vargas, Kevin Duffy, Wolfram Brugger, Maeve O'Reilly, Leigh Wood, David Linch, Karl S Peggs, Carlos Bachier, Elizabeth Lihua Budde, Connie Lee Batlevi, Nancy L. Bartlett, David Irvine, Eleni Tholouli, Wendy Osborne, Kirit M Ardeshna, Martin Pule
Journal: Blood (2023)

Relapse following CD19-directed chimeric antigen receptor T-cells (CAR-T) for relapsed/refractory large B-cell lymphoma (r/r LBCL) is commonly ascribed to antigen loss or CAR-T exhaustion. Multi-antigen targeting and PD-1 blockade are rational approaches to prevent relapse. Here, we test CD19/22 dual-targeting CAR-T (AUTO3) plus pembrolizumab in r/r LBCL as inpatient or outpatient therapy (NCT03289455, https://clinicaltrials.gov/ct2/show/NCT03289455). Endpoints include toxicity (primary) and response rates (secondary). AUTO3 was manufactured for 62 patients using autologous leukapheresis, modified with a bicistronic transgene. 52 patients received AUTO3 (7/52,50x106; 45/52,150-450x106) and 48/52 received pembrolizumab. Median age was 59 years (range,27-83) and 46/52 had stage III/IV disease. Median follow-up was 21.6 months (range,15.1-51.3) at last data cut (Feb 28, 2022). AUTO3 was safe: grade 1-2 and grade 3 CRS affected 18/52 (34.6%) and 1/52 (1.9%) patients, neurotoxicity arose in 4 patients (2/4, grade 3-4), HLH affected 2 patients, and no Pembrolizumab-associated autoimmune sequalae were observed. On this basis, outpatient administration was tested in 20 patients, saving a median of 14 hospital days/patient. AUTO3 was effective: overall response rates were 66% (48.9%, CR; 17%, PR). For patients with CR, median DOR was not reached, with 54.4% (CI: 32.8, 71.7) projected to remain progression-free beyond 12 months after onset of remission. DOR for all responding patients was 8.3 months (95% CI: 3.0, NE) with 42.6% projected to remain progression-free beyond 12 months after onset of remission. Overall, AUTO3 +/- pembrolizumab for r/r LBCL was safe, lending itself to outpatient administration, and delivered durable remissions in 54.4% of complete responders, associated with robust CAR-T expansion. Neither dual-targeting CAR-T nor pembrolizumab prevented relapse in a significant proportion of patients, and future developments include next-generation-AUTO3, engineered for superior expansion/persistence in vivo, and selection of CAR binders active at low antigen densities.
Inhibition of the mitochondrial pyruvate carrier simultaneously mitigates hyperinflammation and hyperglycemia in COVID-19
Authors: Bibo Zhu, Xiaoqin Wei, Harish Narasimhan, Wei Qian, Ruixuan Zhang, In Su Cheon, Yue Wu, Chaofan Li, Russell G. Jones, Mark H. Kaplan, Robert A. Vassallo, Thomas J. Braciale, Lindsay Somerville, Jerry R. Colca, Akhilesh Pandey, Patrick E. H. Jackson, Barbara J. Mann, Connie M. Krawczyk, Jeffrey M. Sturek, Jie Sun
Journal: Science Immunology (2023)

The relationship between diabetes and coronavirus disease 2019 (COVID-19) is bidirectional: Although individuals with diabetes and high blood glucose (hyperglycemia) are predisposed to severe COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can also cause hyperglycemia and exacerbate underlying metabolic syndrome. Therefore, interventions capable of breaking the network of SARS-CoV-2 infection, hyperglycemia, and hyperinflammation, all factors that drive COVID-19 pathophysiology, are urgently needed. Here, we show that genetic ablation or pharmacological inhibition of mitochondrial pyruvate carrier (MPC) attenuates severe disease after influenza or SARS-CoV-2 pneumonia. MPC inhibition using a second-generation insulin sensitizer, MSDC-0602K (MSDC), dampened pulmonary inflammation and promoted lung recovery while concurrently reducing blood glucose levels and hyperlipidemia after viral pneumonia in obese mice. Mechanistically, MPC inhibition enhanced mitochondrial fitness and destabilized hypoxia-inducible factor-1α, leading to dampened virus-induced inflammatory responses in both murine and human lung macrophages. We further showed that MSDC enhanced responses to nirmatrelvir (the antiviral component of Paxlovid) to provide high levels of protection against severe host disease development after SARS-CoV-2 infection and suppressed cellular inflammation in human COVID-19 lung autopsies, demonstrating its translational potential for treating severe COVID-19. Collectively, we uncover a metabolic pathway that simultaneously modulates pulmonary inflammation, tissue recovery, and host metabolic health, presenting a synergistic therapeutic strategy to treat severe COVID-19, particularly in patients with underlying metabolic disease.
Obesity prevention: changing perspectives
Authors: None The Lancet Public Health
Journal: The Lancet Public Health (2023)

March 4 will mark World Obesity Day, an opportunity to reflect and support actions that can help people achieve and maintain a healthy weight. This year's theme "Changing perspectives: Let's talk about obesity" aims to address misconceptions, end stigmas, and shift norms. Simplistic views of weight as a personal choice still remain and drive stigmatisation—affecting confidence, creating barriers to accessing health care, and harming mental and physical health; whereas obesity is complex, multifactorial, with contributing factors embedded in the wider determinants of health.
Synthesising evidence of the effects of COVID-19 regulatory changes on methadone treatment for opioid use disorder: implications for policy
Authors: Noa Krawczyk, Bianca D Rivera, Emily Levin, Bridget C E Dooling
Journal: The Lancet Public Health (2023)

As the USA faces a worsening overdose crisis, improving access to evidence-based treatment for opioid use disorder (OUD) remains a policy priority. Federal regulatory changes in response to the COVID-19 pandemic substantially expanded flexibilities on take-home doses for methadone treatment for OUD. These changes have fuelled questions about the effect of new regulations on OUD outcomes and the potential effect on health of permanently integrating these flexibilities into treatment policy going forward. To aide US policy makers as they consider implementing permanent methadone regulatory changes, we conducted a review synthesising peer-reviewed research on the effect of the flexibilities of methadone take-home policies introduced during COVID-19 on methadone programme operations, OUD patient and provider experiences, and patient health outcomes. We interpret the findings in the context of the federal rule-making process and discuss avenues by which these findings can be incorporated and implemented into US policies on substance use treatment going forward.
Cost-effectiveness of home non-invasive ventilation in patients with persistent hypercapnia after an acute exacerbation of COPD in the UK
Authors: Patrick Brian Murphy, Bernd Brueggenjuergen, Thomas Reinhold, Qing Gu, Laura Fusfeld, Gerard Criner, Thomas F Goss, Nicholas Hart
Journal: Thorax (2023)

Home non-invasive mechanical ventilation (HMV) with home oxygen therapy (HOT) in patients with persistent hypercapnia following an acute exacerbation of chronic obstructive pulmonary disease delays hospital readmission. The economic impact of this treatment is unknown. We evaluated the cost-effectiveness of HMV in the UK healthcare system using data from a previously published efficacy trial. Quality-adjusted life-years (QALYs) were computed from EQ-5D-5L. Accounting for all direct patient costs HOT-HMV was £512 (95%CI £36 to £990) more expensive per patient per year than HOT-alone. This small increase in cost was accompanied by increased quality of life leading to an incremental cost-effectiveness ratio of £10 259 per QALY. HOT-HMV was cost-effective in this clinical population. Trial registration number: NCT00990132 .
Delayed timing of physical therapy initiation increases the risk of future opioid use in individuals with knee osteoarthritis: a real-world cohort study
Authors: Deepak Kumar, Tuhina Neogi, Christine Peloquin, Lee Marinko, James Camarinos, Kosaku Aoyagi, David T Felson, Maureen Dubreuil
Journal: British Journal of Sports Medicine (2023)

Objective We assessed whether late versus early initiation of physical therapy (PT) was related to greater risk of future opioid use in people with knee osteoarthritis (OA) who receive PT. Methods We used Commercial and Medicare Advantage claims data from 1999 to 2018 from American adults with incident knee OA referred for PT within 1 year of diagnosis. We categorised people as opioid naïve or opioid experienced based on prior prescriptions. We examined the association of timing of PT initiation with any and chronic opioid use over 1 year. Results Of the 67 245 individuals with incident knee OA, 35 899 were opioid naïve and 31 346 were opioid experienced. In the opioid naïve group, compared with PT within 1 month, PT 1 to &lt;3, 3 to &lt;6, 6 to &lt;9, 9–12 months from diagnosis was associated with adjusted risk ratio (aRR (95% CIs)) for any opioid use of 1.18 (1.10 to 1.28), 1.49 (1.37 to 1.61), 1.73 (1.58 to 1.89) and 1.93 (1.76 to 2.12), respectively; aRRs (95% CIs) for chronic opioid use were 1.25 (1.01 to 1.54), 1.83 (1.48 to 2.26), 2.29 (1.82 to 2.89) and 2.50 (1.96 to 3.19). Results were similar among opioid experienced; aRRs (95% CIs) for any opioid use were 1.19 (1.14 to 1.24), 1.32 (1.26 to 1.37), 1.39 (1.32 to 1.45) and 1.54 (1.46 to 1.61); aRRs (95% CIs) for chronic opioid use were 1.25 (1.17 to1.34), 1.43 (1.33 to 1.54), 1.53 (1.41 to 1.66) and 1.65 (1.51 to 1.80). Conclusion Compared with PT initiation within 1 month, delayed PT initiation was associated with higher risk of opioid use in people with incident knee OA. The longer the delay in PT initiation, the greater was the risk.
Long-term risk of inflammatory bowel disease after endoscopic biopsy with normal mucosa: A population-based, sibling-controlled cohort study in Sweden
Authors: Jiangwei Sun, Fang Fang, Ola Olén, Mingyang Song, Jonas Halfvarson, Bjorn Roelstraete, Hamed Khalili, Jonas F. Ludvigsson
Journal: PLoS Medicine (2023)

Although evidence suggests a persistently decreased risk of colorectal cancer for up to 10 years among individuals with a negative endoscopic biopsy result (i.e., normal mucosa), concerns have been raised about other long-term health outcomes among these individuals. In this study, we aimed to explore the long-term risk of inflammatory bowel disease (IBD) after an endoscopic biopsy with normal mucosa.In the present nationwide cohort study, we identified all individuals in Sweden with a lower or upper gastrointestinal (GI) biopsy of normal mucosa during 1965 to 2016 (exposed, n = 200,495 and 257,192 for lower and upper GI biopsy, respectively), their individually matched population references (n = 989,484 and 1,268,897), and unexposed full siblings (n = 221,179 and 274,529). Flexible parametric model estimated hazard ratio (HR) as an estimate of the association between a GI biopsy of normal mucosa and IBD as well as cumulative incidence of IBD, with 95% confidence interval (CI). The first 6 months after GI biopsy were excluded to avoid detection bias, surveillance bias, or reverse causation. During a median follow-up time of approximately 10 years, 4,853 individuals with a lower GI biopsy of normal mucosa developed IBD (2.4%) compared to 0.4% of the population references. This corresponded to an incidence rate (IR) of 20.39 and 3.39 per 10,000 person-years in the respective groups or 1 extra estimated IBD case among 37 exposed individuals during the 30 years after normal GI biopsy. The exposed individuals had a persistently higher risk of overall IBD (average HR = 5.56; 95% CI: 5.28 to 5.85), ulcerative colitis (UC, average HR = 5.20; 95% CI: 4.85 to 5.59) and Crohn's disease (CD, average HR = 6.99; 95% CI: 6.38 to 7.66) than their matched population references. In the sibling comparison, average HRs were 3.27 (3.05 to 3.51) for overall IBD, 3.27 (2.96 to 3.61) for UC, and 3.77 (3.34 to 4.26) for CD. For individuals with an upper GI biopsy of normal mucosa, the average HR of CD was 2.93 (2.68 to 3.21) and 2.39 (2.10 to 2.73), compared with population references and unexposed full siblings, respectively. The increased risk of IBD persisted at least 30 years after cohort entry. Study limitations include lack of data on indications for biopsy and potential residual confounding from unmeasured risk or protective factors for IBD.Endoscopic biopsy with normal mucosa was associated with an elevated IBD incidence for at least 30 years. This may suggest a substantial symptomatic period of IBD and incomplete diagnostic examinations in patients with early IBD.
Not all vaping is the same: differential pulmonary effects of vaping cannabidiol versus nicotine
Authors: Tariq A Bhat, Suresh G Kalathil, Maciej L Goniewicz, Alan Hutson, Yasmin Thanavala
Journal: Thorax (2023)

Rationale Vaping has become a popular method of inhaling various psychoactive substances. While evaluating respiratory effects of vaping have primarily focused on nicotine-containing products, cannabidiol (CBD)-vaping is increasingly becoming popular. It currently remains unknown whether the health effects of vaping nicotine and cannabinoids are similar. Objectives This study compares side by side the pulmonary effects of acute inhalation of vaporised CBD versus nicotine. Methods In vivo inhalation study in mice and in vitro cytotoxicity experiments with human cells were performed to assess the pulmonary damage-inducing effects of CBD or nicotine aerosols emitted from vaping devices. Measurements and main results Pulmonary inflammation in mice was scored by histology, flow cytometry, and quantifying levels of proinflammatory cytokines and chemokines. Lung damage was assessed by histology, measurement of myeloperoxidase activity and neutrophil elastase levels in the bronchoalveolar lavage fluid and lung tissue. Lung epithelial/endothelial integrity was assessed by quantifying BAL protein levels, albumin leak and pulmonary FITC-dextran leak. Oxidative stress was determined by measuring the antioxidant potential in the BAL and lungs. The cytotoxic effects of CBD and nicotine aerosols on human neutrophils and human small airway epithelial cells were evaluated using in vitro air–liquid interface system. Inhalation of CBD aerosol resulted in greater inflammatory changes, more severe lung damage and higher oxidative stress compared with nicotine. CBD aerosol also showed higher toxicity to human cells compared with nicotine. Conclusions Vaping of CBD induces a potent inflammatory response and leads to more pathological changes associated with lung injury than vaping of nicotine.
Diagnosis and treatment strategies of the multiligament injured knee: a scoping review
Authors: Navnit S Makaram, Iain R Murray, Andrew G Geeslin, Jorge Chahla, Gilbert Moatshe, Robert F LaPrade
Journal: British Journal of Sports Medicine (2023)

Objective To map the current literature evaluating the diagnosis and treatment of multiligament knee injuries (MLKIs). Design Scoping review. Data sources Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews and Arksey and O’Malley frameworks were followed. A three-step search strategy identified relevant published literature comprising studies reporting on at least one aspect in the diagnosis or treatment of MLKI in adults. Data were synthesised to form a descriptive analysis and thematic summary. Results Overall, 417 studies were included. There was a substantial chronological increase in the number of studies published per year, with 70% published in the last 12 years. Of included studies, 128 (31%) were narrative reviews, editorials or technical notes with no original data. The majority of studies (n=239, 57%) originated from the USA; only 4 studies (1%) were of level I evidence. Consistent themes of contention included clinical assessment, imaging, operative strategy, timing of surgery and rehabilitation. There was a lack of gender and ethnic diversity reported within patient groups. Conclusions There remains insufficient high-level evidence to support definitive management strategies for MLKI. There is considerable heterogeneity in outcome reporting in current MLKI literature, precluding robust comparison, interpretation and pooling of data. Further research priorities include the development of expert consensus relating to the investigation, surgical management and rehabilitation of MLKI. There is a need for minimum reporting standards for clinical studies evaluating MLKI.
Interim Estimates of 2022–23 Seasonal Influenza Vaccine Effectiveness — Wisconsin, October 2022–February 2023
Authors: Huong Q. McLean, Joshua G. Petrie, Kayla E. Hanson, Jennifer K. Meece, Melissa A. Rolfes, Gregg C. Sylvester, Gabriele Neumann, Yoshihiro Kawaoka, Edward A. Belongia
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

In the United States, 2022-23 influenza activity began earlier than usual, increasing in October 2022, and has been associated with high rates of hospitalizations among children* (1). Influenza A(H3N2) represented most influenza viruses detected and subtyped during this period, but A(H1N1)pdm09 viruses cocirculated as well. Most viruses characterized were in the same genetic subclade as and antigenically similar to the viruses included in the 2022-23 Northern Hemisphere influenza vaccine (1,2). Effectiveness of influenza vaccine varies by season, influenza virus subtype, and antigenic match with circulating viruses. This interim report used data from two concurrent studies conducted at Marshfield Clinic Health System (MCHS) in Wisconsin during October 23, 2022-February 10, 2023, to estimate influenza vaccine effectiveness (VE). Overall, VE was 54% against medically attended outpatient acute respiratory illness (ARI) associated with laboratory-confirmed influenza A among patients aged 6 months-64 years. In a community cohort of children and adolescents aged <18 years, VE was 71% against symptomatic laboratory-confirmed influenza A virus infection. These interim analyses indicate that influenza vaccination substantially reduced the risk for medically attended influenza among persons aged <65 years and for symptomatic influenza in children and adolescents. Annual influenza vaccination is the best strategy for preventing influenza and its complications. CDC recommends that health care providers continue to administer annual influenza vaccine to persons aged ≥6 months as long as influenza viruses are circulating (2).